Bis/para(amino-loweralkyleneoxy)phenyl/alkanols and the salts thereof

ABSTRACT

THIS APPLICATION RELATES TO ALCOHOLS OF THE GENERAL FORMULA   1,3-DI(R-),2-((R1-)2-N-(LOWER ALKYLENE)-O-),5-((3,5-   DI(R-),4-((R1-)2-N-(LOWER ALKYLENE)-O-)PHENYL)-   C(-(LOWER ALKYL))(-(CH2)N-CH2-OH)-)BENZENE   AND TO ACID ADDITION SALTS THEREOF. THESE SUBSTANCES INHIBIT CHOLESTEROL BIOSYNTHESIS AND AID IN THE REGULATION OF CHOLESTEROL IN THE BLOOD.

United States Patent Ofiice 3,809,720 Patented May 7, 1974 US. Cl.260-570 R Claim! ABSTRACT OF THE DISCLOSURE This application relates toalcohols of the general formula R lower It lower alkyl lower at/N-alkylne i3 O-elkylene- \R 1 H n 1 2) R HIOH and to acid additionsalts thereof. These substances inhibit cholesterol biosynthesis and aidin the regulation of cholesterol in the blood.

This application is a continuation-in-part of application Ser. No.793,612 filed I an. 22, 1969, which is in turn a continuation-in-part ofapplication Ser. No. 566,245, filed July 19, 1966, which is in turn acontinuation-in-part of application Ser. No. 288,630, filed June 18,1963, all of which are now abandoned.

SUMMARY OF THE INVENTION This invention relates to new compounds of theformula R R 131% R R lower A lower N-alkylene-O 0-alkylene-N\ R 4 Am). BR

HlQH v and to acid addition salts thereof.

The symbols in Formula I have the following meanings:

R represents hydrogen, lower alkyl, lower alkoxy or halo.

R represents hydrogen, lower alkyl, phenyl-lower alkyl,

hydroxyalkyl.

n is 1 t0 6.

The lower alkyl groups represented by the symbols referred to aboveinclude straight and branched chain saturated aliphatic groups havingfrom one to about seven carbon atoms such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, amyl, isoamyl, hexyl, and the like.Methyl and ethyl are preferred. The lower alkoxy groups contain alkylgroups of the same character attached to an oxygen atom. Similarly, thelower alkylene groups are divalent radicals of the same kind.

Each of the four halogens is contemplated by the term halo, but chlorineand bromine are preferred.

In the basic nitrogen containing radicals represented by each group.

each R can be the same or different and represents hydrogen, loweralkyl, hydroxy-lower alkyl, phenyl-lower alkyl and N-(loweralkyl)phenyl(lower alkyl), forming such basic groups as amino, loweralkylamino, e.g., methylamino, ethylamino, di(lower alkyl)amino, e.g.,dimethylamino, methylethylamino, dipropylamino (hydroxy-loweralkyl)amino, e.g., hydroxyethylamino, di(hydroxy-lower alkyl)amino,e.g., di(hydroxyethyl)amino, phenyl(lower alkyl) amino, e.g.,benzylamino, phenethylamino, N- (lower alkyl)phenyl-(lower alkyl)amino,e.g., N-methylbenzylamino, and the like.

DETAILED DESCRIPTION OF THE INVENTION The new compounds of thisinvention may be produced from esters of the formula (III) R lower Ralkyl HO ---OK i H7) l sented by hal, although it is not necessary to belimited to those two.

The resulting ester has the formula R iiigi R l lower ([3 lower N-a.lkylene-0 O-alkyleue-N r) R Alternatively, the ester of Formula HIcan be reacted with a dihalide (hal-lower alkylene-hal) to form ahaloalkylene ether which is reacted with an amine to form the ester ofFormula V.

Hydrolysis of the compound of Formula V yields the corresponding acid (R=H) Treatment of the ester or acid of Formula V with a reducing agentsuch as lithium aluminum hydride yields an alcohol of Formula I.

The bases of Formula I form acid addition salts by reaction with thecommon inorganic and organic acids. Such inorganic salts as thehydrohalides, e.g., hydrobromide, hydrochloride, hydroiodide, sulfates,nitrates, phosphates, borates, etc., and organic salts as acetate,oxalate, tartrate, malate, citrate, succinate, benzoate, pamoate,ascorbate, salicylate, theophyllinate, camphorsulfonate,alkanesulfonate, e.g., methanesulfonate, arylsulfonate, e.g.,benzenesulfonate, toluenesulfonate and the like are also within thescope of the invention. It is frequently convenient to effect thepurification of the product by forming the acid salt. The base may beobtained therefrom by neutralization with an alkali hydroxide such assodium hydroxide.

The new compounds of this invention are therapeutical- 1y activesubstances which are useful as hypochloestermic agents. They inhibitcholesterol biosynthesis and regulate the cholesterol in the blood ofwarm-blooded animals such as rats and the like. Thus they are useful inthe treatment of conditions such as atherosclerosis. These products maybe administered orally or parenterally, e.g., at a dosage level of 2 to40 mg./kg./day in single or divided doses, preferably 1 to mg./kg.orally two to four times daily, in the form of tablets, capsules,elixirs, injectables, or the like by incorporating the base of Formula Ior a physiologically acceptable acid addition salt thereof in aconventional vehicle prepared with suitable vehicle, excipient,lubricant, flavor, etc., according to accepted pharmaceutical practice.

The following examples are illustrative of the invention. Alltemperatures are expressed on the centigrade scale.

EXAMPLE 1 (A) 4,4-bis [p- (2-diethylaminoethoxy) phenyl] valeric acid,ethyl ester A solution of 99.0 (0.32 mole) of4,4-bis(phydroxyphenyl)valeric acid, ethyl ester in 200 ml. ofdimethylformamide is treated portionwise with 30 g. (0.63 mole) sodiumhydride (50 percent dispersion). The reaction is exothermic and thetemperature of the mixture is maintained below 60 by cooling. Aftercompletion of the addition of the hydride, the slurry is heated to 80,cooled to 40 and treated with 290 ml. of 2.2 N 2-diethylaminoethylchloride (0.63 mole) in toluene. This mixture is gradually heated andthen maintained at 100-110 for three hours. The major portion of thesolvent is removed under reduced pressure; the residue is treated with200 ml. of water and then extracted twice with 600 ml. portions ofether. The ether phases are combined and shaken with (l) 100 ml. of 5percent sodium bicarbonate solution and (2) 50 ml. of water. The etherphase is dried over magnesium sulfate, charcoal is added and the mixturefiltered. The filtrate is concentrated under reduced pres' sure to give146 g. of syrupy material. A solution of 125.7 g. of the above materialin 600 ml. of ether is added to a cold solution of 50 ml. ofconcentrated hydrochloric acid in 300 ml. of water. The mixture isshaken, the organic phase is discarded and the aqueous phase is washedand treated with a cold solution of 30 g. of sodium hydroxide in 100 ml.of water. The organic phase is extracted with 400 ml. portions of ether(three times). The ether phases are combined, dried over magnesium,sulfate, filtered and the filtrate concentrated under reduced pressureto give 91.3 g. (66 percent) of pale orange syrupy product.

(B) 4 (4-bis [p- (2-diethylaminoethoxy )pheny'l1pentanol The ester ofExample 1(A) (25 g.) is dissolved in ether and added dropwise to anethereal solution of 1.5 g. of lithium aluminum hydride. The mixture isrefluxed for two hours, cooled and treated with a small quantity ofsodium hydroxide solution. The ethereal solution of the product, 4,4bis[p-(Z-diethylaminoethoxy)phenyl]pentanol, is decanted from theinorganic salts, dried over magnesium sulfate, filtered and the solventevaporated to give 17.7 g. of the product.

EXAMPLE 2 (A) 4,4-bis[p-(Z-dimethylaminoethoxy)phenyl]valeric acid,methyl ester Sixty grams (0.2 mole) of 4-4-bis(p-hydroxyphenyl)- valericacid, methyl ester, g. (0.42 mole) of 50 percent sodium hydride and 250ml. of 1.7 N Z-dimethylaminoethyl chloride (0.42 mole) in toluene arereacted in 175 ml. of dimethylformamide as described in Example 1(A).The bulk of solvents is removed in vacuo on a rotary evaporator at 70and the cooled residue is shaken with 150 ml. of water and 400 ml. ofether. The layers are separated and the aqueous phase extracted twicemore with 200 ml. portions of ether. The combined ether layers arewashed with 100 ml. of water and added to a cold solution of 38 ml. ofconcentrated hydrochloric acid in 400 m1. of water to obtain crudehydrochloride. After shaking, the layers are separated and the aqueousphase is washed wiht ether, cooled and treated with a cold solution of20 g. of sodium hydroxide in ml. of water. The liberated base of theether gives 48.5 g. (55 percent) of syrupy material.

(B) 4,4-bis [p- Z-dimethylaminoethoxy) phenyl] pentanol By treating4,4-bis [p-(Z-dimethylaminoethoxy)phenyl] valeric acid, methyl esteraccording to the procedure of Example 1(B'), 4,4-bis[p-(2-dimethylaminoethoxy)phenyl]pentanol is obtained. Treatment of thisproduct, dissolved in ethanol, with two equivalents of hydrogen chloridegives the dihydrochloride salt.

EXAMPLE 3 I 3,3-bis [p-(2-diethylaminoethoxy) phenyl] butanol Followingthe procedure of Example 1(A) but substituting an equivalent quantity of3,3-bis (p-hydroxyphenyl) butyric acid, ethylester for the4,4-bis(p-hydroxyphenol) valeric acid, ethyl ester, 3,3-bis[p-(Z-diethylaminoethoxy) phenyl]butyric acid, ethyl ester is obtained.Treatment of this product according to the procedure of Example 1(B)gives the butanol.

EXAMPLE 4 5,5-bis[p-(Z-diethylaminoethoxy) phenyl1hexanol Following theprocedure of Example 1(A) but substituting an equivalent quantity of5,5-bis(p-hydroxyphenyl) hexanoic acid, propyl ester for the 4,4-bis(p-hydroxyphenyl)valeric acid, ethyl ester,5,5-bis[p-(Z-diethylaminoethoxy)phenyl]hexanoic acid, propyl ester isobtained. Treatment of this product according to the procedure ofExample 1(B) gives the hexanol.

EXAMPLES 5 TO 9 Using the procedure of Example 1 but replacing the4,4-bis(p-hyd roxyphenyl)valeric acid, ethyl ester by the correspondingesters of (A) 4,4-bis(3-methyl-4-hydroxyphenyl)valeric acid, (B)4,4-bis(3-ethoxy-4-hydroxyphenyl)valeric acid, (C)4,4-bis(3-chloro-4-hydroxyphenyl)valeric acid, (D)4,4-bis(3,5-dimethyl-4-hydroxyphenyl)valeric acid, (E)4,4-bis(3-bromo-4-hydroxyphenyl)valeric acid,

respectively, there is obtained, respectively:

4, 4-bis [4- (2-diethylaminoethoxy) -3-methylphenyl] valeric acid, ethylester.

4,4-bis [4- 2-diethylaminoethoxy) -3-ethoxyphenyl] valeric acid, ethylester.

4,4-bis [4- (Z-diethylaminoethoxy) -3 -ch1orophenyl] valeric acid, ethylester.

4,4-bis [4- Z-diethylaminoethoxy) -3 ,5 -dimethylphenyl] valeric acid,ethyl ester.

4, 4-bis [4- (Z-diethylamino ethoxy) -3 -bromophenyl] valeric acid,ethyl ester.

Treatment of each of the foregoing esters according to the procedure ofExample 1(B) gives the following products:

5 EXAMPLES 10 TO 13 Using the procedure of Example 1, but replacing theN-Z-diethylaminoethyl chloride by the aminoalkylene halide shown incolumn 1 of Table I and replacing the 4,4-bis(p-hydroxy phenyl) valericacid, ether ester with the acid ester shown in column 2 of Table I,there is obtained the esters which are treated as described in Example1(B) to form the products of the invention shown in column 3 of Table I.

2. A compound according to claim 1 wherein each R is hydrogen and each Ris lower alkyl.

3. A compound according to claim 1 wherein each R is hydrogen, each R islower alkyl, each lower alkylene group has two carbon atoms, the loweralkyl group has one carbon atom and n is 2.

4. A compound according to claim 3 wherein each R is ethyl.

5. A compound according to claim 3 wherein each R is methyl.

TABLE I R R lower R lower alkyl N-alkylene-Hel Q 3} HO- OH R H Ii (02):; R

OOR

Ex. No. B Lower alkylene Hal B Lower alkyl R n 10 i-CaH1 (CH2): Cl CH;CH; CH:

11 CH B C H 0 F 2) r z a CH; 0211s 12 CH I Cl C H C H 4 r a); a a a I 13HOCzHr- CH1 Cl Br 03H! 04H. 1

R lower R alkyl R lower a} lower /Nalkylene0 Oalkylene-N R I]; (Hz). l R

H1OH

Ex. No. B Lower alkylene B Lower alkyl 11 10 i-CsHy (CH2): CH: CH: 5

11 Q (CHIN CzHtO CH1 12 Q (CH2)! C1 CzHl 4 CzHq 13-..-'..' HOCzHr- CHIBr C H 1 What is claimed is: References Cited A the frmula UNITED STATESPATENTS 1 R mi 3,075,014 1/1963 Palopoli et a1. 260-570 1 l Ev{ ;f3,320,217 5/1967 Ledmcer 260 507.7 X l 2) I R 55 ROBERT V. HINES,Primary Examiner HzOH wherein R is hydrogen, lower alkyl, lower alkoxy,or halo; each R is the same or different and is selected phenyl (loweralkyl); n is an integer from 1 to 6 and acid addition salts thereof.

US. Cl. X.R.

